N-nitrosopiperazine



preferably sodium hydroxide,

United States Patent Ng-NITROSGPIPERAZINE Rudolph G. Berg, New London, Conn, assignor to Chas. Pfizer & Co., Inc., Brooklyn, N.Y., a corporation of Delaware I No Drawing. Application May 9, 1957 i i Serial No 658,023

7 Claims. or. 260-268) This invention relates to an improved process for producing N monorsubstituted piperazines and N,N-unsymmetrically disubstituted p-iperazines, as well as to a novel intermediate for their production and the method of producing this intermediate.

In accordance with the prior art, a number of methods have been suggested for blocking one of the imino groups of piperazine in order to permit the introduction of a desired substituent at the other nitrogen atom while avoiding the undesired production of N,N-symrnetrical1y disubstituted piperazine. These blocking methods for the production of mono-substituted piperazines have a number of common difiiculties. For example, carrbethoxylation with ethylchioroformate involves the use of an expensive reagent, is a difiicult reaction, and subsequent removal of the blocking group with acid is difiicult. When acetylation is employed, the yields are poor and it is difiic ult to isolate the monoaoetylated" product. fienlzylation necessitates the use of an expensivereagent, afford s low yields and requires catalytic hydrogenation for removal of the blocking group.

I In accordance with the present invention, it has been expectedly discovered that a nitroso group may be introduced to obtain N-nitrosopiperazine in substantially high-yields providing certain conditions are fulfilled, and that this compound is an exceedingly useful intermediate for the production of pure N-mono-substituted and N,N'- unsymmetrically disubstituted piperazines. The advantages of N- nitro sopiperazine as an intermediate are manifold: for instance, yields of the order of from 80 to 90% N fnitrosopiperazine are obtained in accordance with the process of the present invention; the reagents, preferably a mineral acid, an alkali metal nitrite and an alkali metal hydroxide, are relatively cheap and easily obtained; control of reaction conditions is neither difficult nor expensive equipment required; the yields of desired N-mono substituted piperazines are of the order of 90% or more; and the nit'roso blocking group may be easily removed, e.gi, by hydrolyzing with an inexpensive acid, such as hydroehloric acid, or such acid and urea.

In accordance with the process of the present invention for producing N-nitrosopiperazine, this valuable int ert nediate may be prepared by treating an aqueous solution of piperazine with nitrous acid while maintaining the solution at a temperature in the range of from about 30 to about 35 C., adjusting the acidity of the meto a pH of at least 4 by the addition of a base, such as an alkali metal or alkaline earth metal hydroxide, separating the relatively minor amount of insoluble N,N-dinitrosopiperazine byproduct and then recovering Nwnit-rosopiperazine. Recovery of the latter is most conveniently accomplished by organic solvent extraction of the resulting aqueous filtrate which had been made strongly alkaline, concentration of the organic extract if desired, and subsequent dis- .til a on n r duc d su e- 2,907,767 Patented Qct. 6, 1959 A variation of this process relates to the separation of the insoluble N,N'-dinitro sopiperazine at any pH before the N-nitrosopiperazine oils out; or it may be found equally desirable to separate the desired product from the by-product by vacuum distillation. Furthermore, the small amount of insoluble N,N'-dinitrosopiperaz ine presout can even be allowed to remain in the reaction mixture without causing any difliculty in subsequent steps of the process. i

A preferred embodiment of the process of this invention involves utilization of an aqueous solution of piperazine which is acidified with a mineral acid, such as nitric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid or hydrobromic acid, while maintaining the solution at a temperature below about 50 C. to obtain a solution of a piperazine diacid salt. In order to obtain a high yield in this step, an excess of mineral acid is, of course, preferably employed. This solution is then treated with a water-soluble inorganic nitrite salt,

preferably an alkalimetal or alkaline earth metal nitrite, and most desirably sodium nitrite in view of its availability and cheapness, while maintaining the solution at a temperature in the range of from about -30 to about 35 (3.; the preferred optimum temperature is in the range of from about l5 to about 25 C. The amount of water-soluble inorganic nitrite salt employed is not critical, but a stoic hiornetrically equivalent amount is, of

t course, preferred in order to convert a maximum amount .of the piperazine diacid salt to the desired N-nitrosopiper- -azine without production of substantial amounts of N,N-

Following pH adjustment, the insoluble N,N-dinitroso.- piperazine by-product is preferably removed, and N- nitrosopiperazine recovered from the combined aqueous filtrate and washings by the method outlined above after said filtrate has been first made strongly alkaline, although any pH value over 7 is suificient. A preferred solvent for extraction is chloroform, but other halogenated drocarbon solvents, such as methylene chloride, carbon tetrachloride, ethylene dichloride and trichloroethylenfe are satisfactory.

The i l w ng eauat qn ustrat t e p o ess clescribed herein for the produotion of N-nitrpsopipera zine, the subsequent introduction of a substituent group, such a alkyl a s/1 ara kyl y lo k l n an; et n fina l he tempt-a of the P QS am o afiotd a cerreactant and N-nitrosopiperazine are soluble.

'ture being maintained at 5 v I 'tion; the reaction mixture was then subsequently stirred thydroxide without to and specifically illustrated in US. Patent No. 2,415,785 of February 11, 1947:

It will be understood that in place of RX, reactants such may be employed, R being the substituent group as set forth above; examples of these compounds include dimethyl sulfate, dimethyl sulfite, etc.

For the purpose of introducing the substituent group R at the other imino nitrogen of N-nitrosopiperazine,

the reactant containing the desired R substituent is introduced into a solution of said intermediate, the solvent for this solution being inert and one in which both Preferred solvents include dioxane, lower alkanols, e.g., methanol,

.ethanol,gisobutanol, etc., lower aliphatic ketones, e.g., .acetone, methyl ethyl ketone, etc., and water, and mixtures thereof. For the purpose of neutralizing the byproduct acid produced during condensation, a base such as an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metalcarbonate or an alkali metal bicarbonate is present in the reaction mixture.

Subsequent to formation of the N-substituted-N-ni- .trosopiperazine, the nitroso group may be removed by treatment with concentrated hydrochloric acid or hot,

strong hydrochloric acid in the presence of urea. Re-

moval of the nitroso group by means of hydrogenation in the presence of Raney Nickel catalyst may also be employed, except in. the case where an aralkyl group is and the examples hereinafter are for the purpose of illustration only and not limiting to the scope thereof.

Example I To 540 ml. of water in a five liter, three-necked flask equipped with a stirrer, thermometer, dropping funnel and vent to the atmosphere were added 1,163 g. (6.0 moles) of piperazine hexahydrate. Stirring was then initiated and the temperature held below 50 C. while 1.14 liters (13.8 equivalents) of concentrated hydrochloric acid were added. The mixture was then cooled to 0 by means of an ice-salt-water bath and a solution of 436.2 g. (approximately 6.0 moles) of approximately 95% pure sodium nitrite in 840 ml. of water was added during the course of about 55-70 minutes, the tempera- C. throughout the addifor about another 15 minutes at this same temperature.

- Upon completionof this reaction, the mixture was .treated with 120 ml..of cornmercial 50% aqueous sodium any further cooling (resulting pH At thisv point, the insoluble N,N';dinitroa t, g V

by-product was filtered from the reaction sopiperazine mixture, and the resulting cake washed with about 150 ml. of water. The filtrate and washings were then combined and made strongly alkaline by slowly adding 1.86 liters of 50% aqueous sodium hydroxide. The desired product was then extracted from the aqueous solution with two 1.5 liter portions and one 600 ml. portion of chloroform. The separated chloroform layers were then combined and subsequently filtered through a film of diatomateous earth in order to remove suspended aqueous droplets. The organic filtrate was then concentrated by evaporating the solvent on a steam cone under reduced pressure, and the residual liquid was distilled in vacuo. The yield of product boiling at -95 C./1.0:0.4 mm. amounted to 572 g. (82%). N-nitrosopiperazine is a liquid having characteristic yellow color, A max at 214 mu (e n l.5000i0.0005. It is almost odorless, and it is completely miscible with water and polar organic solvents.

Analysis.Calcd. for C H N O: C, 41.73; H, 7.88; neut. equiv., 115.1. Found: C, 41.11; H, 7.11; neut. equiv., 115.8.

Example II The same procedure as described in Example I was followed here except that the nitrosation was carried out at 15 C., whereby an 81% yield of N-nitrosopiperazine was obtained; when the nitrosation was conducted at 25 C., a 65% yield of product was obtained. In a similar manner, the reaction was conducted at various other temperatures in the range of from about 30 C. to about 35 C., and N-nitrosopiperazine was produced in each instance.

Example 111 To a solution of 117.5 g. of N-nitrosopiperazine in 700 ml. of methyl alcohol and 108 ml. of water containing 86 g. of sodium bicarbonate was added 192.6 g. of m-xylyl bromide during the course of one hour, the temperature being maintained at 25-30 C. throughout the addition. The reaction mixture was then stirred for an additional two hours at this temperature and subsequently refluxed for four hours. After the excess methanol solvent had been removed by evaporation under reduced pressure, the cooled residue was treated with four equivalents of2.34 N hydrochloric acid. The strongly acidic medium containing the intermediate N-nitroso-N-xylylpiperazine was then contacted with two equivalents of urea which were added at 40-50 C. during the course of 30 minutes; a vigorous evolution of gas was observed throughout the ad- 'dition. The resulting solution was then refluxed for four hours, cooled, and the pH adjusted to 6.2 with 50% sodium hydroxide. The desired product was then extracted from the aqueous alkaline solution with benzene; the resultant aqueous phase was then readjusted to pH 12.5 with 50% sodium hydroxide and twice extracted with benzene to obtain further product. The benzene extracts were then combined and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the benzene was removed from the filtrate by evaporation under reduced pressure. The residual liquid was then subjected to distillation in vacuo and there was obtained an 82% yield of m-xylylpiperazine, B.P. 122- 128 C. at 3mm; n 1.5431.

Example IV III was again followed.

Example V The procedures described in Examples III and IV were employed here except that the alkylating agent used Was p-chlorobenzhhydrylchloride and the product obtained was N-p-chlorobenzhydrylpiperazine. In a similar manner, the alkating agent employed was benzyl chloride, ethyl bromide, hexyl bromide, propyl iodide, cyclopentyl iodide, acetyl chloride, dimethyl sulfite and dimethyl sulfate; in each case, the corresponding N-substituted piperazine was obtained.

Example VI An N-monosubstituted piperazine of this invention pre pared as described above, such as N-Xylylpiperazine and N-p-chlorobenzhydrylpiperazine, was alkylated according to the procedure of Clarke, Gillespie and Wiesshauss (J. Amer. Chem Soc. 55, 4571 (1933)), employing any of the alkylating agents previously mentiored. After liberation of the base, the reaction mixture was treated with benzoylchloride to remove any N-rnono-substituted piperazine that had remained unreacted. The basic material was again liberated by alkali and the desired product distilled in vacuo. Further purification of the resulting N,N-unsymmetrically disubstituted piperazine was achieved by crystallizing the dihydrochloride salt from an absolute alcohol-ether solution.

Similarly, the same products may be obtained by treating the Nmono-substituted piperazine according to the same procedure described in Example III.

What is claimed is:

1. The process for the production of an intermediate useful in the synthesis of N-rnono-substituted and N,N- unsymmetrically disubstituted piperazine compounds,

' which comprises treating an aqueous solution of piperazine with nitrous acid while maintaining the solution at a temperature in the range of from about 30 to about 35 C. and immediately thereafter adjusting the solution to a pH in the range of from about 4 to 7.

2. The process for the production of N-nitrosopiperazine, which comprises contacting an aqueous piperazine solution with a mineral acid while maintaining the solution at a temperature below about 50 C., treating the resulting piperazine diacid salt containing solution with a water-soluble inorganic nitrite salt while maintaining the solution at a temperature in the range of from about -30' to about 35 C., immediately thereafter adjusting the solution to a pH in the range of from about 4 to about 7 and finally recovering the N-nitrosopiperazine.

3. The process as claimed in claim 2 wherein the Watersoluble inorganic nitrite salt is chosen from the group consisting of alkali metal nitrites and alkaline earth metal nitrites.

4. The process as claimed in claim 2 wherein N-nitrosopiperazine is recovered by separating the insoluble N,N'- dinitrosopiperazine, adjusting the aqueous filtrate to a pH of at least 7 and subsequently extracting with a halogen ated hydrocarbon solvent.

5. In the process for the production of a N-nitroso-N- mono-substituted piperazine from piperazine, the improvement which comprises treating an aqueous solution of piperazine with nitrous acid while maintaining the solution at a temperature in the range of from about -30 to about 35 C. and immediately thereafter adjusting the solution to a pH in the range of from about 4 to 7 to thereby block one piperazine imino nitrogen with a nitroso group and then introducing the desired mono substituent at the other imino nitrogen of the piperazine molecule.

6. In the process for the production of a N-mono-substituted piperazine from piperazine, the improvement which comprises treating an aqueous solution of piperazine with nitrous acid while maintaining the solution at a temperature in the range of from about 30" to about 35 C. and immediately thereafter adjusting the solution to a pH in the range of from about 4 to 7 to thereby block one piperazine imino nitrogen with a nitroso group, then introducing the desired mono-substituent at the other imino nitrogen of the piperazine molecule, and subsequently removing the nitroso blocking group.

7. In the process for the production of a N,N'-unsymmetrically disubstituted piperazine, the improvement which comprises treating an aqueous solution of piperazine with nitrous acid while maintaining the solution at a temperature in the range of from about -30 to about 35 C. and immediately thereafter adjusting the solution to a pH in the range of from about 4 to 7 to thereby block one piperazine imino nitrogen with a nitroso group, then introducing a desired mono substituent at the other imino nitrogen of the piperazine molecule, subsequently removing the nitroso blocking group, other and different substituent group for the active hydrogen atom of the remaining free imino group.

References Cited in the file of this patent FOREIGN PATENTS Beilstein: vol. 23, p. 7, 1st supplement (1936).

and then substituting an- 

1. THE PROCESS FOR THE PRODUCTION OF AN INTERMEDIATE USEFUL IN THE SYNTHESIS OF N-MONO-SUBSTITUTED AND N, N''UNSYMMETRICALLY DISUBSTITUTED PIPERAZNE COMPOUNDS WHICH COMPRISES TREATING AN AQUEOUS SOLUTION OF PIPERAZINE WITH NITROUS ACID WHILE MAINTAINING THE SOLUTION AT A TEMPERATURE IN THE RANGE OF FROM ABOUT -30* TO ABOUT 35*C. AND IMMEDIATELY THEREAFTER ADJUSTING THE SOLUTION TO A PH IN THE RANGE OF FROM ABOUT 4 TO
 7. 